The proposed new studies extend those in mice with fibromyalgia-type musculoskeletal hyperalgesia ("Urocortin &Musculoskeletal Hyperalgesia";12/01/08-11/30/13;Larson, P.I.) to studies in humans. The new collaboration between Drs. Larson and Pardo brings together a basic scientist (Larson), who has a long- standing interest in the mechanism of pain transmission with a focus on that seen in patients with fibromyalgia, and a clinical neuroscientist (Pardo), who has expertise in PET imaging. The original proposal was to determine the effect of specific stress hormones on musculoskeletal pain models in mice. The new studies focus on the unique distribution of such pain in patients with fibromyalgia (near the trunk and proximally rather than distally and on the extremities) based on the tendency for cold stress to enhance the symptoms of fibromyalgia. Brown adipose tissue is located near the trunk and proximal extremities-- i.e., in supraclavicular areas and atop sympathetic ganglia in the trunk. Stress activates brown adipose tissue via sympathetic nerves with collaterals to surrounding skin and muscle. We hypothesize that this enhanced sympathetic tone causes sympathetically maintained pain in the skin and muscle surrounding brown adipose tissue. The BIRT research goal is to test this hypothesis by determining whether the pain of fibromyalgia, measured by palpation, nociceptive flexor reflexometry, and established rating scales, correlates with the volume (MRI) or glucose metabolic activity (tissue uptake of fluordeoxyglucose PET) of brown adipose tissue in fibromyalgia patients compared to controls. In these individuals, we will assess whether pain is temporarily relieved by dietary manipulations inhibiting brown adipose activity, or whether the pain is worsened by exposure to cold increasing brown adipose tissue activity. As in the parent grant, samples will be taken to monitor the concentrations of stress hormones (CRF and urocortins I, II and III) in fibromyalgia patients compared to healthy controls, as suggested by the reviewers of the original RO1 proposal. These studies will be the first to test the hypothesis of sympathetically mediated metabolism in brown adipose tissue and the collateral effects upon the pain in related muscles and skin in fibromyalgia syndrome. They can provide a novel inroad toward developing novel assessment and therapeutic strategies. PUBLIC HEALTH RELEVANCE: According to NIAMS statistics, 1 in 73 (1.35%) or approximately 3.7 million Americans suffer from fibromyalgia syndrome. Stress enhances the symptoms of fibromyalgia, but the mechanism by which this occurs is unknown. We hypothesize that stress enhances sympathetic tone to brown adipose tissue as well as to collaterals that innervate the surrounding skin and muscle in areas that overlap with the distribution of fibromyalgia pain. If the amount or activity of brown adipose tissue (determined using FDG PET and MRI) differs in patients with fibromyalgia from that in controls, this will, for the first time, identify the regulation of brown adipose tissue as a potential contributor to fibromyalgia symptoms. Identification of pathways that cause pain in these patients will allow us to test potential therapies and clinical interventions that relieve the symptoms of fibromyalgia.